PROJECT SUMMARY Understanding the impact of alcohol consumption on bone health is important because alcohol influences bone metabolism and over half of the adult population in the United States drinks alcoholic beverages. Low to moderate levels of alcohol consumption are generally associated with beneficial skeletal effects while chronic alcohol abuse predisposes individuals to bone fractures. The long-term goal of our research is to delineate the primary mechanisms mediating the divergent skeletal effects of low/moderate and heavy alcohol consumption. An appreciation of the precise effects and mechanisms of action of alcohol on bone metabolism is important because of the enormous economic, social and personal burden associated with poor bone health. Progress in understanding the actions of alcohol on bone metabolism are hampered by (1) the extreme difficulty in performing intervention studies in humans, (2) limitations of commonly used animal models, (3) failure to adequately consider alcohol?s effects on tissue and organ systems that impact bone, and (4) difficulty in accurately replicating human drinking behavior in animals. The studies proposed in this R01 application will overcome limitations of human and prior animal studies by using a non-human primate (monkey) model for voluntary alcohol consumption that mimics the full range of human drinking behavior. We will use linear regression models, multivariate linear regression models, machine learning, and systems analysis to establish the impact of pattern of alcohol consumption (none, light/moderate, binge, heavy and very heavy) on bone metabolism in rhesus (Macaca mulatta; n=105) and cynomolgus (Macaca fascicularis; n=86) macaques in the context of sex, age and alcohol-induced perturbations in tissue and organ systems that can influence bone. We will identify the latter perturbations by determining the effect of alcohol on specific protein (e.g., peptide hormones and cytokines) and small molecule (e.g., steroid hormones) effectors in blood. Our central hypothesis, based in part on our preliminary data in rats, macaques and humans, is that changes in the blood levels of bone-active hormones and cytokines, derived from several tissues/organs, in response to alcohol intake act in concert to modulate bone cell number and activity. To test our hypothesis, we propose the following two Specific Aims: Specific Aim 1: Define the correlative relationships between the quantity and pattern of alcohol consumption and bone in male and female macaques. Specific Aim 2: Define the correlative relationships among blood ethanol levels, key bone active hormones and cytokines, and biochemical markers of bone turnover in male and female macaques. At the completion of this project, we expect to have established that the magnitude of skeletal response to alcohol will correlate with changes in serum biochemical markers of bone turnover which, in turn, will correlate with changes in circulating levels of specific hormones and cytokines. The primary positive impact of our anticipated findings is identification of key underlying factors responsible for the complex, context-dependent actions of alcohol on bone metabolism.